rs17832998

Variant names:

• chr14-58646014-C-T
• rs17832998
• NM_001079520.2:c.1280C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-58646014-C-T
• chr14-58646014-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001079520.2(DACT1):​c.1280C>T​(p.Ala427Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,906 control chromosomes in the GnomAD database, including 75,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6256 hom., cov: 34)
  • Exomes 𝑓: 0.30 (69121 hom.)
• Consequence: DACT1 NM_001079520.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0790
• Publications: 29 publications found

Genes affected

DACT1 (HGNC:17748): (dishevelled binding antagonist of beta catenin 1) The protein encoded by this gene belongs to the dapper family, characterized by the presence of PDZ-binding motif at the C-terminus. It interacts with, and positively regulates dishevelled-mediated signaling pathways during development. Depletion of this mRNA from xenopus embryos resulted in loss of notochord and head structures, and mice lacking this gene died shortly after birth from severe posterior malformations. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

DACT1 Gene-Disease associations (from GenCC):

• Townes-Brocks syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Townes-Brocks syndrome 2

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003786713).
• BP6: Variant 14-58646014-C-T is Benign according to our data. Variant chr14-58646014-C-T is described in ClinVar as Benign. ClinVar VariationId is 1255448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079520.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT1	NM_001079520.2	MANE Select	c.1280C>T	p.Ala427Val	missense	Exon 4 of 4	NP_001072988.1	Q9NYF0-2
	DACT1	NM_016651.6		c.1391C>T	p.Ala464Val	missense	Exon 4 of 4	NP_057735.2
	DACT1	NR_046093.2		n.1060C>T		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DACT1	ENST00000395153.8	TSL:5 MANE Select	c.1280C>T	p.Ala427Val	missense	Exon 4 of 4	ENSP00000378582.3	Q9NYF0-2
	DACT1	ENST00000335867.4	TSL:1	c.1391C>T	p.Ala464Val	missense	Exon 4 of 4	ENSP00000337439.4	Q9NYF0-1
	DACT1	ENST00000707126.1		c.1280C>T	p.Ala427Val	missense	Exon 4 of 4	ENSP00000516754.1	Q9NYF0-2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42669 AN: 152086 Hom.: 6258 Cov.: 34

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.300

GnomAD2 exomes AF: 0.279 AC: 69781 AN: 250366 AF XY: 0.289

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.304 AC: 444368 AN: 1461702 Hom.: 69121 Cov.: 84 AF XY: 0.307 AC XY: 222987 AN XY: 727162

African (AFR) AF: 0.260 AC: 8718 AN: 33478

American (AMR) AF: 0.152 AC: 6789 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7145 AN: 26136

East Asian (EAS) AF: 0.232 AC: 9198 AN: 39700

South Asian (SAS) AF: 0.357 AC: 30775 AN: 86256

European-Finnish (FIN) AF: 0.232 AC: 12358 AN: 53264

Middle Eastern (MID) AF: 0.333 AC: 1921 AN: 5768

European-Non Finnish (NFE) AF: 0.314 AC: 348944 AN: 1111990

Other (OTH) AF: 0.307 AC: 18520 AN: 60392

GnomAD4 genome AF: 0.280 AC: 42674 AN: 152204 Hom.: 6256 Cov.: 34 AF XY: 0.275 AC XY: 20477 AN XY: 74410

African (AFR) AF: 0.262 AC: 10898 AN: 41558

American (AMR) AF: 0.220 AC: 3359 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 922 AN: 3472

East Asian (EAS) AF: 0.247 AC: 1277 AN: 5166

South Asian (SAS) AF: 0.341 AC: 1641 AN: 4812

European-Finnish (FIN) AF: 0.228 AC: 2415 AN: 10604

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21062 AN: 67974

Other (OTH) AF: 0.296 AC: 625 AN: 2112

Alfa AF: 0.302 Hom.: 31311

Bravo AF: 0.276

TwinsUK AF: 0.317 AC: 1175

ALSPAC AF: 0.320 AC: 1232

ESP6500AA AF: 0.261 AC: 1148

ESP6500EA AF: 0.319 AC: 2747

ExAC AF: 0.285 AC: 34577

Asia WGS AF: 0.267 AC: 928 AN: 3478

EpiCase AF: 0.317

EpiControl AF: 0.321

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Townes-Brocks syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.6
DANN	Uncertain	0.97
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.079
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.057
Sift	Benign	0.045	D
Sift4G	Benign	0.12	T
Polyphen		0.033	B
Vest4		0.032
MPC		0.19
ClinPred		0.013	T
GERP RS		2.4
Varity_R		0.059
gMVP		0.16
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17832998; hg19: chr14-59112732; COSMIC: COSV60019927; COSMIC: COSV60019927;